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Capture-based targeted sequencing using a T-cell control in myeloid malignancies and idiopathic cytopenias
No full textWe report on a study of next-generation sequencing in 257 patients undergoing investigations for cytopenias. We sequenced bone marrow aspirates using a target enrichment panel comprising 82 genes and used T cells from paired blood as a control. One hundred and sixty patients had idiopathic cytopenias, 81 had myeloid malignancies and 16 had lymphoid malignancies or other diagnoses. Forty-seven of the 160 patients with idiopathic cytopenias had evidence of somatic pathogenic variants consistent with clonal cytopenias. Only 39 genes of the 82 tested were mutated in the 241 patients with either idiopathic cytopenias or myeloid neoplasms. We confirm that T cells can be used as a control to distinguish between germline and somatic variants. The use of paired analysis with a T-cell control significantly reduced the time molecular scientists spent reporting compared to unpaired analysis. We identified somatic variants of uncertain significance (VUS) in a higher proportion (24%) of patients with myeloid malignancies or clonal cytopenias compared to less than 2% of patients with non-clonal cytopenias. This suggests that somatic VUS are indicators of a clonal process. Lastly, we show that blood depleted of lymphocytes can be used in place of bone marrow as a source of material for sequencing.Published version, accepted version (12 month embargo), submitted versionRD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Expanding the phenotype and genotype spectrum of TAOK1 neurodevelopmental disorder and delineating TAOK2 neurodevelopmental disorder
No full textPURPOSE: The thousand and one kinase (TAOK) proteins are a group of serine/threonine-protein kinases involved in signaling pathways, cytoskeleton regulation, and neuronal development. TAOK1 variants are associated with a neurodevelopmental disorder (NDD) characterized by distinctive facial features, hypotonia, and feeding difficulties. TAOK2 variants have been reported to be associated with autism and early-onset obesity. However, a distinct TAOK2-NDD has not yet been delineated. METHODS: We retrospectively studied the clinical and genetic data of individuals recruited from several centers with TAOK1 and TAOK2 variants that were detected through exome and genome sequencing. RESULTS: We report 50 individuals with TAOK1 variants with associated phenotypes, including neurodevelopmental abnormalities (100%), macrocephaly (83%), and hypotonia (58%). We report male genital anomalies and hypoglycemia as novel phenotypes. Thirty-seven unique TAOK1 variants were identified. Most of the missense variants clustered in the protein kinase domain at residues that are intolerant to missense variation. We report 10 patients with TAOK2 variants with associated phenotypes, including neurodevelopmental abnormalities (100%), macrocephaly (75%), autism (75%), and obesity (70%). CONCLUSION: We describe the largest cohort of TAOK1-NDD to date, to our knowledge, expanding its phenotype and genotype spectrum with 30 novel variants. We delineated the phenotype of a novel TAOK2-NDD associated with neurodevelopmental abnormalities, autism, macrocephaly, and obesity.RDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Optimised human stool sample collection for multi-omic microbiota analysis
No full textTo accurately define the role of the gut microbiota in health and disease pathogenesis, the preservation of stool sample integrity, in terms of microbial community composition and metabolic function, is critical. This presents a challenge for any studies which rely on participants self-collecting and returning stool samples as this introduces variability and uncertainty of sample storage/handling. Here, we tested the performance of three stool sample collection/preservation buffers when storing human stool samples at different temperatures (room temperature [20 °C], 4 °C and - 80 °C) for up to three days. We compared and quantified differences in 16S rRNA sequencing composition and short-chain fatty acid profiles compared against immediately snap-frozen stool. We found that the choice of preservation buffer had the largest effect on the resulting microbial community and metabolomic profiles. Collectively analysis confirmed that PSP and RNAlater buffered samples most closely recapitulated the microbial diversity profile of the original (immediately - 80 °C frozen) sample and should be prioritised for human stool microbiome studies.Published version, accepted version, submitted versionJournal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Considerations of morphometry and phenotypes in modern knee arthroplasty
No full textAs advancements in total knee arthroplasty progress at an exciting pace, two areas are of special interest, as they directly impact implant design and surgical decision making. Knee morphometry considers the three-dimensional shape of the articulating surfaces within the knee joint, and knee phenotyping provides the ability to categorize alignment into practical groupings that can be used in both clinical and research settings. This annotation discusses the details of these concepts, and the ways in which they are helping us better understand the individual subtleties of each patient's knee.Not hel
Comparison of laparoscopic cholecystectomy in children at paediatric centres and adult centres: a systematic review and meta-analysis
No full textINTRODUCTION: Paediatric laparoscopic cholecystectomy (LC) is performed by both paediatric and adult surgeons. The aim of this review was to compare outcomes at paediatric centres (PCs) and adult centres (ACs). METHODS: A literature search was conducted, in accordance with PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines, for papers published between January 2000 and December 2020. Statistical analysis was performed using Stata(®) version 16 (StataCorp, College Station, TX, US). RESULTS: A total of 92 studies involving 74,852 paediatric LCs met the inclusion criteria. Over half (59%) of the LCs were performed at ACs. No significant differences were noted in the male-to-female ratio, mean age or mean body mass index between PCs and ACs. The main indications were cholelithiasis (34.1% vs 34.4% respectively, p=0.83) and biliary dyskinesia (17.0% vs 23.5% respectively, p<0.01). There was no significant difference in the median inpatient stay (2.52 vs 2.44 days respectively, p=0.89). Bile duct injury was a major complication (0.80% vs 0.37% respectively, p<0.01). Reoperation rates (2.37% vs 0.74% respectively, p<0.01) and conversion to open surgery (1.97% vs 4.74% respectively, p<0.01) were also significantly different. Meta-analysis showed no significant difference in overall complications (p=0.92). CONCLUSIONS: The number of LCs performed, intraoperative cholangiography use and conversion rates were higher at ACs whereas bile duct injury and reoperation rates were higher at PCs. Despite a higher incidence of bile duct injury at PCs, the incidence at both PCs and ACs was <1%. In complex cases, a joint operation by both paediatric and adult surgeons might be a better approach to further improve outcomes. Overall, LC was found to be a safe operation with comparable outcomes at PCs and ACs.Not permittedThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
The Getting It right First Time (GIRFT) programme in urology; rationale and methodology
No full textThe Getting It Right First Time (GIRFT) programme is a quality improvement initiative covering the National Health Service in England. The programme aims to standardise clinical practices and improve patient and system level outcomes by utilising data-driven insights and clinically-led recommendations. There are GIRFT workstreams for every medical and surgical specialty, including urology. Defining features of the GIRFT methodology are that it is clinically led by experienced clinicians, data-driven, and specialty specific. Each specialty workstream conducts deep-dive visits to every hospital, analysing performance data and engaging with clinicians and management to identify and share improvement priorities. For urology, GIRFT has completed deep-dive visits and published reports outlining priority areas for development. Reports include recommendations pertaining to streamlining care pathways, reducing the acuity of care environments, enhancing emergency services, optimising utilisation of outpatient services, and workforce training and utilisation. The GIRFT academy provides guides for implementing best practices specific to priority areas of care. These include important disease pathways, and GIRFT-advocated innovations such as urology investigation units and urology area networks. GIRFT offers clinical transformation, cost reduction, equity in access to care, and leaner models of care that are often more environmentally sustainable. Evaluation efforts of the programme have focussed on assessing the adoption of GIRFT recommendations, understanding barriers to change, and modelling the climate impact of advocated practices.Published version, accepted version (12 month embargo), submitted versionRDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Patients' Preferences for Cytoreductive Treatments in Newly Diagnosed Metastatic Prostate Cancer: The IP5-MATTER Study
No full textBACKGROUND AND OBJECTIVE: Cytoreductive treatments for patients diagnosed with de novo synchronous metastatic hormone-sensitive prostate cancer (mHSPC) confer incremental survival benefits over systemic therapy, but these may lead to added toxicity and morbidity. Our objective was to determine patients' preferences for, and trade-offs between, additional cytoreductive prostate and metastasis-directed interventions. METHODS: A prospective multicentre discrete choice experiment trial was conducted at 30 hospitals in the UK between December 3, 2020 and January 25, 2023 (NCT04590976). The individuals were eligible for inclusion if they were diagnosed with de novo synchronous mHSPC within 4 mo of commencing androgen deprivation therapy and had performance status 0-2. A discrete choice experiment instrument was developed to elicit patients' preferences for cytoreductive prostate radiotherapy, prostatectomy, prostate ablation, and stereotactic ablative body radiotherapy to metastasis. Patients chose their preferred treatment based on seven attributes. An error-component conditional logit model was used to estimate the preferences for and trade-offs between treatment attributes. KEY FINDINGS AND LIMITATIONS: A total of 352 patients were enrolled, of whom 303 completed the study. The median age was 70 yr (interquartile range [IQR] 64-76) and prostate-specific antigen was 94 ng/ml (IQR 28-370). Metastatic stages were M1a 10.9% (33/303), M1b 79.9% (242/303), and M1c 7.6% (23/303). Patients preferred treatments with longer survival and progression-free periods. Patients were less likely to favour cytoreductive prostatectomy with systemic therapy (Coef. -0.448; [95% confidence interval {CI} -0.60 to -0.29]; p < 0.001), unless combined with metastasis-directed therapy. Cytoreductive prostate radiotherapy or ablation with systemic therapy, number of hospital visits, use of a day-case" procedure, or addition of stereotactic ablative body radiotherapy did not impact treatment choice. Patients were willing to accept an additional cytoreductive treatment with 10 percentage point increases in the risk of urinary incontinence and fatigue to gain 3.4 mo (95% CI 2.8-4.3) and 2.7 mo (95% CI 2.3-3.1) of overall survival, respectively. CONCLUSIONS AND CLINICAL IMPLICATIONS: Patients are accepting of additional cytoreductive treatments for survival benefit in mHSPC, prioritising preservation of urinary function and avoidance of fatigue. PATIENT SUMMARY: We performed a large study to ascertain how patients diagnosed with advanced (metastatic) prostate cancer at their first diagnosis made decisions regarding additional available treatments for their prostate and cancer deposits (metastases). Treatments would not provide cure but may reduce cancer burden (cytoreduction), prolong life, and extend time without cancer progression. We reported that most patients were willing to accept additional treatments for survival benefits, in particular treatments that preserved urinary function and reduced fatigue."Published version, accepted version (12 month embargo)Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Establishing a standardised approach for the measurement of neonatal noxious-evoked brain activity in response to an acute somatic nociceptive heel lance stimulus
No full textBACKGROUND: Electroencephalography (EEG) can be used in neonates to measure brain activity changes that are evoked by noxious events, such as clinically required immunisations, cannulation and heel lancing for blood tests. EEG provides an alternative approach to infer pain experience in infants compared with more commonly used behavioural and physiological pain assessments. Establishing the generalisability and construct validity of these measures will help corroborate the use of brain-derived outcomes to evaluate the efficacy of new or existing pharmacological and non-pharmacological methods to treat neonatal pain. This study aimed to test whether a measure of noxious-evoked EEG activity called the noxious neurodynamic response function (n-NRF), that was originally derived in a sample of term-aged infants at the Oxford John Radcliffe Hospital, UK, in 2017, can reliably distinguish noxious from non-noxious events in two independent datasets collected at University College London Hospital and at Royal Devon & Exeter Hospital. We aimed to reproduce three published results that use this measure to quantify noxious-evoked changes in brain activity. We used the n-NRF to quantify noxious-evoked brain activity to test (i) whether significantly larger noxious-evoked activity is recorded in response to a clinical heel lance compared to a non-noxious control heel lance procedure; (ii) whether the magnitude of the activity evoked by a noxious heel lance is equivalent in independent cohorts of infants; and (iii) whether the magnitude of the noxious-evoked brain activity increases with postmenstrual age (PMA) in premature infants up to 37 weeks PMA. Positive replication of these studies will build confidence in the use of the n-NRF as a valid and reliable pain-related outcome which could be used to evaluate analgesic efficacy in neonates. The protocol for this study was published following peer review (https://doi.org/10.17605/OSF.IO/ZY9MS). RESULTS: The n-NRF magnitude to a noxious heel lance stimulus was significantly greater than to a non-noxious control heel lance stimulus in both the UCL dataset (n = 60; mean difference .88; 95% confidence interval (CI) .64-1.13; p < .0001) and the Exeter dataset (n = 31; mean difference .31; 95% CI .02-.61; p = .02). The mean magnitude and 90% bootstrap confidence interval of the n-NRF evoked by the heel lance did not meet our pre-defined equivalence bounds of 1.0 ± .2 in either the UCL dataset (n = 72; mean magnitude 1.33; 90% bootstrapped CI 1.18-1.52) or the Exeter dataset (n = 35; mean magnitude .92, 90% bootstrapped CI .74-1.22). The magnitude of the n-NRF to the noxious stimulus was significantly positively correlated with PMA in infants up to 37 weeks PMA (n = 65; one-sided Pearson's R, adjusted for site: .24; 95% CI .06-1.00; p = .03). CONCLUSIONS: We have reproduced in independent datasets the findings that the n-NRF response to a noxious stimulus is significantly greater than to a non-noxious stimulus, and that the noxious-evoked EEG response increases with PMA. The pre-defined equivalence bounds for the mean magnitude of the EEG response were not met, though this might be due to either inter-site differences such as the lack of calibration of devices between sites (a true negative) or underpowering (a false negative). This reproducibility study provides robust evidence that supports the use of the n-NRF as an objective outcome for clinical trials assessing acute nociception in neonates. Use of the n-NRF in this way has the potential to transform the way analgesic efficacy studies are performed.UnknownJournal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
The Current Role of Imaging in the Diagnosis of Inflammatory Bowel Disease and Detection of Its Complications: A Systematic Review
No full textInflammatory bowel disease (IBD) encompasses complex gastrointestinal (GI) conditions, primarily Crohn's disease (CD) and ulcerative colitis (UC), requiring precise imaging for effective diagnosis and management of complications. This systematic review aimed to evaluate the current role of imaging modalities in diagnosing IBD and detecting related complications. The review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We performed a literature search using text words and controlled vocabulary applying Boolean operators AND," "OR," with various combinations on databases such as PubMed, Embase, and Cochrane Library. The search targeted open-access articles involving humans, with full-text available, and published in the English Language from 2005 to 2024. The quality of the included studies was assessed using the Cochrane Risk-of-Bias (RoB) checklist. Our search process identified 127 records from Cochrane (39), Embase (29), and PubMed (59). After removing 98 irrelevant records, 29 underwent further screening. Five were excluded as they involved irrelevant problems or outcomes, leaving us with 24 reports with full text, all of which were accessible. Following the eligibility assessment, two more reports were excluded due to inaccessibility, and 22 studies were included in the final analysis. The risk of bias and methodological quality assessment revealed that out of 22 studies analyzed, five (23%) had a high risk of bias, while 13 (59%) were classified as moderate risk, and four (18%) showed low risk. This distribution highlights a predominance of moderate-risk studies in research on imaging in IBD, emphasizing the need for enhanced study designs in future investigations. Our findings revealed the varying effectiveness of imaging modalities in diagnosing complications of CD and UC. Magnetic resonance enterography (MRE) stands out as the preferred method for CD due to its high sensitivity and noninvasive nature. In contrast, colonoscopy remains the gold standard for UC, providing direct visualization of mucosal lesions. While techniques like ultrasound and capsule endoscopy offer valuable insights, they have limitations that may affect their utility in certain cases."RDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Less than full-time as a new normal in paediatric training in the UK
No full textPublished version, accepted version, submitted versionRDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted